Stem cells in the treatment of infertility
Premature ovarian failure (POF) occurs in women under the age of 40 y with primary or secondary hypergonadotropic amenorrhea and accompanied by estrogen deficiency in 75% of cases. None of the women with primary amenorrhea have been reported to ovulate or conceive with their own oocytes, but more than a third of the women were pregnant atleast once before developing hypergonadotropic POF. It is speculated that lack of follicular renewal may be caused by age-associated exhaustion of specific memory cells in the lymphoid system and bone marrow that are necessary to generate effector cells migrating to ovaries and stimulating transformation of OSE cells into primitive granulose and germ cells. POF may be caused by delayed ovarian development during immunological adaptation, by earlier termination of immunological adaptation or by cytostatic chemotherapy affecting both the existing pool of primary follicles and committed Ovary specific mesenchymal cells(O-SMCs) required for the follicular renewal (Reviewed by Bukovsky A et al.,2006).
POF is also often associated with follicular resistance to gonadotropins called hypergonadotropic amenorrhea where ovaries contain normal primary and antral follicles not responding to gonadotropins by production of estrogen(Reviewed by Bukovsky A et al., 2006).
Studies with laboratory animal models have showed that there are two types of POF with primary and antral follicles within the ovaries. The first persistent ovarian immaturity can be induced by inhibition of ovarian development (i.e inhibition of androgen receptor expression with estrogens) during immunological adaptation. The second premature ovarian ageing can be induced by the acceleration of ovarian development with androgens(Bukovsky et al., 2006;Bukovsky A et al., 2000; Bukovsky A et al., 2002).
Studies by Bukovsky et al., 2005 have shown that cultures of Ovarian surface epithelium showed cells of oocyte phenotype in 4-5 days. A well defined nuclear envelope of the oocyte was seen. Isolated oocyte type cells exhibited germinal vesicle breakdown and some of them showed characteristics of secondary oocytes with surface ZP expression, expulsion of polar body and poor nuclear/cytoplasmic separation(Bukovsky et al., 2005). The ability of OSC cultures to produce new oocytes from ovaries lacking follicular renewal suggests that Ovariam surface epithelium (OSE) cells retain the potential to differentiate but fail to do so in vivo. As the putative stimulatory potential of o-SMCs is absent, uncommitted mesenchymal cells (u-MCs) may exhibit a suppressive effect. For eg: CD8 T lymphocytes which are predominant type of T-cells present in epithelial and other non lymphoid tissues (Beagley and husband.,1998) can function as effector or suppressor cells(Doherty et al., 1997). Marked changes in circulating subsets of T Cells are described in postmenopausal women and women with POF (Giglio et al., 1994).
Studies done in mice...